In the United States, while it is legal for physicians to prescribe
drugs for "off-label" indications (uses for which the drugs do
not have Food and Drug Administration approval), it is largely--though
not entirely--illegal for drug manufacturers to promote off-label uses
of their drugs to physicians. In recent months, the rules against
off-label marketing have been rigorously enforced: in October, Allergan
reached a $375 million settlement over off-label promotion of Botox; in
September, Novartis settled an off-label marketing dispute for $422.5
million, and Forest Laboratories settled one for $313 million. These
were only the latest in a series of criminal and civil settlements on
off-label promotion, the most dramatic being last year's $2.3
billion settlement by Pfizer. And there are more to come: the Justice
Department just joined a private whistleblower suit against Wyeth--an
indication that the government thinks the suit has merit. Lawyers for
the whistleblowers predict recovery in the hundreds of millions of
dollars. (1)

But even as the Justice Department was busily prosecuting off-label
marketers, the FDA last year finalized a guidance document that expands
manufacturers' off-label marketing opportunities and makes them
more difficult to oversee. The nonbinding guidance, originally advanced
by the Bush administration and finalized under President Obama, permits
drug company marketers to give physicians reprints of published
scientific articles describing new off-label uses for their drugs. (2)
This marketing is permitted regardless of whether the manufacturer
intends to seek on-label status for the use being marketed. And in a
departure from previous policy, the distributed articles no longer need
advance vetting by the FDA.

For the uninitiated, this strange, simultaneous mix of strict
enforcement and rule-liberalization may raise a number of puzzling
policy questions. At the most basic level, one may wonder why off-label
use of drugs is permitted at all. But if it is permitted, why prosecute
firms for encouraging physicians to engage in a legal activity? And why
worry about the distribution of published scientific articles to
physicians?

To get a grip on this set of issues, one must understand the
phenomenon of off-label drug use. Such use is in fact extremely common,
particularly in certain areas of medical practice. There are a number of
reasons why this is so.

The most complex of these reasons has to do with the fact that
obtaining FDA approval for any given drug use is both costly and
time-consuming. Manufacturers want the approval process to move as
quickly as possible, maximizing the number of years their drugs can be
on the market before the patent expires, at which point they face
competition from generic manufacturers and their profit margins drop.
Manufacturers therefore concentrate on gaining regulatory approval for
those indications for which they have, or can most easily gather, the
best data in the shortest time. Oncology drugs, for example, are often
approved only for particular varieties of cancer. If the manufacturer
wants to market its drug for an additional use, the law requires that it
go to the trouble and expense of demonstrating the drug's safety
and efficacy for that new use.

But in an ideal financial scenario, a drug manufacturer bypasses
the process of adding new uses to the drug's label. If it can get
its drug to market for one use but sell the drug for many uses, it saves
the expense of gaining regulatory approval for those other uses. Hence
the temptation to promote off-label uses. But a certain amount of
off-label drug utilization would undoubtedly also occur without any
effort on the manufacturer's part. Medical researchers and
practicing physicians understand that the mechanisms that make a given
drug work against one sort of cancer, for example, may work against
others as well. Physicians regularly experiment with off-label drug use
for their patients, and some independent researchers study off-label
efficacy. These factors lead to widespread off-label prescribing.
Experts have estimated that as many as 50 percent of cancer drug
prescriptions are for off-label indications. (3)

Another factor driving off-label use is that there are entire
populations in which new drugs are seldom tested. Drug companies are
understandably reluctant to test new drugs on pregnant women or
children. If a drug trial in such populations were to go wrong,
liability could be large and publicity disastrous. Nor are many drugs
tested in the very old: their metabolic rates differ from those of
younger, healthy people, they often have multiple medical conditions and
conflicting drug prescriptions, and they may drop out of a costly study
prematurely due to illness or death. No surprise, then, that
pediatricians, obstetricians, and geriatricians often prescribe drugs
that have only been tested in and approved for use by young and
middle-aged adults.

Finally, off-label drug use is driven by the fact that
pharmaceutical science moves on well after all incentive for regulatory
approval has vanished. Once a drug has lost its patent protection, its
profit margin may not be high enough to warrant the trouble and expense
of getting FDA approval for it, even for the most promising of new uses.

Off-label drug utilization can certainly be of great benefit to
patients. It is no exaggeration to say that "In oncology,
pediatrics, geriatrics, obstetrics, and other practice areas, patient
care could not proceed without off-label prescribing." (4) Medicare
and private insurance companies recognize this and routinely reimburse
for off-label drug utilization.

But off-label drug utilization has important downsides. There are
risks inherent in the off-label use of any drug because the drug has not
gone through the same rigorous testing for that use as it has for its
on-label indication. While many off-label uses of drugs are
scientifically valid, the evidence for off-label utilization is quite
variable, both in quantity and in quality. And any off-label use carries
risks--even when the departure from the label is as "simple"
as prescribing for children a drug approved for use in adults. (Just
adjusting a dosage for weight differences may not address other
important differences between how children and adults metabolize the
drug.) Finally, there is ample evidence that physicians' knowledge
of the scientific validity of various off-label drug uses is poor. (5)

The main governmental efforts at controlling off-label drug use
have been aimed at regulating off-label drug marketing. But marketing is
speech, and however laudable their goal of ensuring patients'
safety, marketing regulations may offend the First Amendment, which
protects nondeceptive commercial speech. The drug companies argue that
they have every right to share factual information about their
drugs' potential off-label uses with physicians; there is nothing
wrong with nondeceptive commercial promotion of legal activity. Critics
respond that, without someone in the room to monitor the marketing
conversation, there is no guarantee that what's said is not
deceptive. The drug industry points to the recent spate of off-label
marketing suits as evidence of unfair and unpredictable prosecution, (6)
while critics regard the suits as further evidence of industry greed and
unscrupulousness.

The dispute over the recent change in FDA guidance governing the
distribution of scientific reprints to physicians illustrates the
complexity of this safety-versus-free-speech clash. First, that the new
FDA policy is framed as a nonbinding guidance document rather than as a
binding regulation is itself probably a nod to the free-speech rights of
drug marketers. Second, the terms of the guidance are a series of
compromises between the goals of respecting free speech and ensuring
scientific validity. The guidance lets drug marketers give physicians
peer-reviewed articles on off-label drug use. The articles must come
from journals with conflict-of-interest disclosure policies; articles
from in-house drug company journals won't do. They may not be
marked up in any way and must be accompanied by the FDA label for the
drug in question. No other drug promotional material can be attached.
The studies in question must be "scientifically sound." All of
these restrictions appear to be aimed at permitting free speech while
assuring quality. (7) Critics, predictably, allege that they will do no
such thing. The new policy, they argue, will permit marketers to
cherry-pick from among numerous published articles and use only the most
positive studies. At least one critic has voiced the fear that less
prestigious journals now have an incentive to accept new studies
favoring off-label drug use because those studies will bring in
lucrative reprint orders from drug marketers. (8) Finally, a few
notorious cases have illustrated that the bulk of the available
peer-reviewed literature on a particular drug was produced by the drug
manufacturer and disseminated by unethical practices such as
"ghostwriting"; if the medical literature is itself deceptive,
then distribution of reprints from that literature is only more of the
same.

Given the complexities of the free-speech problem, it may be more
fruitful for the government to refocus its attention on the regulation
of conduct. Recent commentators have suggested, for example, that the
FDA could be empowered to require manufacturers to gather data on
particularly common or problematic off-label uses. (9) Less intrusively,
the government could expand its own efforts to evaluate common off-label
uses and publicize lists of the best- and worst-supported among them.
Finally, some have proposed that independent researchers, disease
groups, medical specialty societies, or government entities could be
authorized to seek regulatory approval for off-label uses of the drugs,
perhaps under special guidelines. (10) All of these reforms would help
increase the safety of off-label use.

(2.) Food and Drug Administration, "Good Reprint Practices for
the Distribution of Medical Journal Articles and Medical or Scientific
Reference Publications on Unapproved New Uses of Approved Drugs and
Approved or Cleared Medical Devices," January 2009,
http://www.fda.gov/RegulatoryInformation/Guidances/ucm125126.htm.